We Have Some Trouble with Special Characters and Displaying Monographs. 22.09.2018 ATC Code: G03FA17 Classification

We have some trouble with special characters and displaying monographs. 22.09.2018

ATC code: G03FA17 Classification: PRP - Probably porphyrinogenic Substance: Drospirenone and estrogen Rationale for risk classification: Estrogens and progestogens are considered as potentially porphyrinogenic substances and are known to have caused porphyric attacks in susceptible carriers of acute porphyria. Both pharmacodynamic and pharmacokinetic properties can explain the triggering effect in acute porphyria. Studies have shown that these hormones can affect CYP enzymes by induction and mechanism-based inhibition. Although these effects are described to a limited extent in drug-drug interactions studies in general, it is likely that they have a role in a probable upregulation of the heme biosynthesis. Chemical description: Drospirenone is a spironolactone derivative. Estradiol is a natural steroid hormone. Therapeutic characteristics: Continuous monophasic hormone replacement therapy (HRT). It is administered orally. Side effects or other pharmacodynamic effetcs of relevance to acute porphyria: A suggested hypothesis for the porphyrinogenic potential of progestins (Thunell 2016) is that they activate the mPRalpha-PGRMC2 receptor complex (Thomas 2013), which is accompanied by heme binding (Rohe 2009), and may therefore result in a heme drain. A decreased cellular heme pool may then upregulate ALAS-1 (Besur 2014). In addition, the heme-sensing receptor, Rev-erb-alpha, will sense the decreased level of the regulatory heme pool and reduce its repressor effect on PGC-1alpha (Wu 2009). PGC-1alpha may then co-activate FoxO1 and NRF-1, with subsequent induction of the ALAS-1 gene (Handschin 2005).

An in vitro study found that estrogens might directly activate ALAS-1 (Du Plessis 2009). In the presence of estrogen, the estrogen receptor-alpha (ER-alpha) binds to estrogen receptor elements (ERE) in the ALAS-1

Copyright 2007-2018 The Drug Database. All rights reserved.Page 1/6 promotor and results in an elevated transcription of ALAS-1 and thereby causing a subsequent increase in the rate of the entire heme biosynthesis pathway. Metabolism and pharmacokinetics: Estradiol is predominantly metabolized in the liver to estrone and then to estriol (SPC). CYP1A2 and 3A4 are involved in the hydroxylation of estradiol to estriol, which is further glucuronidated. Estradiol and its metabolites are mainly excreted by the kidneys (SPC).

Estradiol is not found to be an inhibitor of CYP2C9, CYP2C19 and CYP3A4, and compared to ethinyl estradiol, it is less likely to cause mechanism-based inhibition due to the lack of an acetylenic group (Laine 2003).

Estradiol is listed as an activator of human PXR (Honkakoski 2003, Mnif 2007) and has been found to induce CYP2A6 in vitro (Higasi 2007). Drospirenone is metabolized by opening of the lactone ring, and by reduction and subsequent sulfatation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone is a weak to moderate inhibitor of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 (SPC). Progesterone and synthetic progestogens activate PXR (Kliewer 1998). Progestogens and estradiol are not listed as significant inducers of CYP 3A4 in most interaction databases (Preissner 2010, NOMA, Lexi-Interact, The Danish Health and Medicines Authority, Micromedex).

Results from clinical studies suggest that the increased hormonal levels in pregnancy have the potential to alter hepatic cytochrome P450 drug metabolism (Anderson 2005). Also, in vitro studies have shown increased CYP mRNA after exposing hepatocytes to progesterone and estradiol levels equal to the high hormonal levels typically seen in the third trimester of pregnancy (Choi 2013). Hormonal therapy generally leads to a much lower plasma concentration relative to the levels of endogenous hormones in pregnancy and may explain the lack of observed significant effects of administered hormones on CYP 3A4 in vivo. However, since both estradiol and the progestin component have the potential to induce ALAS1 through PXR activation and at the same time cause inhibition of CYP 3A4, this may explain the absence of observed pharmacokinetic drug-drug interactions. For an evaluation of the porphyrinogenicity of these drugs it is important to realize that the inhibitory effect can mask the inductive power and that an

Copyright 2007-2018 The Drug Database. All rights reserved.Page 2/6 increased de novo synthesis of CYP3A4 can take place irrespective of negative results from in vivo DDI-studies. The effects of concomitant induction and inhibition have in general been discussed by Wei et al. for other drugs (Wei 2016). Since CYP3A4 quantitatively is the largest CYP isoenzyme, an increased de novo synthesis of CYP3A4, although masked, will give an upregulation of ALAS-1and thereby a higher flux through the heme biosynthesis. Such a mechanism can possibly in part explain the observed porphyrinogenic effects of these drugs.

Studies have shown that women with acute porphyria have an altered 5alfa-reductase steroid metabolism and it is suggested that this may lead to a diversion from the 5 alfa reductase pathway to formation of 5beta steroid metabolites that may be more potent inductors of ALAS1 (Innala 2012, Anderson 1979, Jacobs 2005). Published clinical experience: It is from clinical observations well known that progestogens and estrogens have a role in precipitating acute porphyric attacks (Andersson 2003, Kauppinen 1992, Bonkovsky 2014). References: Andersson C, Innala E, et al. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med. 2003 Aug;254(2):176-83.

Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989-1008.

Anderson KE, Bradlow HL, et al. Studies in porphyria. VIII. Relationship of the 5 alpha-reductive metabolism of steroid hormones to clinical expression of the genetic defect in acute intermittent porphyria. Am J Med. 1979 Apr;66(4):644-50.

Besur S, Hou W, et al. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Nov 3;4(4):977-1006.

Bonkovsky HL, Maddukuri VC et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med. 2014 Dec;127(12):1233-41.

Copyright 2007-2018 The Drug Database. All rights reserved.Page 3/6 Du Plessis N, Kimberg M, et al. Functional analysis of the 5' regulatory region of the 5-aminolevulinate synthase (ALAS1) gene in response to estrogen. Cell Mol Biol (Noisy-le-grand). 2009 Jul 1;55(2):20-30.

Higashi E, Fukami T, et al. Human CYP2A6 is induced by estrogen via estrogen receptor. Drug Metab Dispos. 2007 Oct;35(10):1935-41. Epub 2007 Jul 23.

Handschin C, Lin J, et al. Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell. 2005 Aug 26;122(4):505-15.

Honkakoski P, Sueyoshi T, et al. Drug-activated nuclear receptors CAR and PXR. Ann Med. 2003;35(3):172-82.

Innala E, BÃ¤ckstrÃ¶m T et al. Women with acute intermittent porphyria have a defect in 5?-steroid production during the menstrual cycle. Acta Obstet Gynecol Scand. 2012 Dec;91(12):1445-52.

Jacobs MN, Nolan GT, Hood SR. Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR). Toxicol Appl Pharmacol. 2005 Dec 1;209(2):123-33

Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore). 1992 Jan;71(1):1-13.

Kliewer SA, Moore JT, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. 1998 Jan 9;92(1):73-82.

Lexi-Interact in UpToDate: Drug interaction program. http://www.micromedexsolutions.com/ (Accessed 23.08.2017).

Mnif W, Pascussi JM, et al. Estrogens and antiestrogens activate hPXR. Toxicol Lett. 2007 Apr

MicromedexÂ® 2.0 (online). Drug Interactions). http://www.helsebiblioteket.no/ (23.08.2017).

Norwegian medicines agency (NOMA). Find medicine. http://www.legemiddelverket.no/interaksjonssok (Accessed: 23.08.2017).

Preissner S, Kroll K, rt al. SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43.

Rohe HJ, Ahmed IS, et al. PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharmacol Ther. 2009 Jan;121(1):14-9.

The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Angeliq. http://www.medicines.org.uk/EMC/. (Last edition: 31.08.2017).

The Danish Health and Medicines Authority. The drug interaction database. http://www.interaktionsdatabasen.dk/ (Accessed: 23.08.2017).

Thomas P, Pang Y, et al. Enhancement of cell surface expression and receptor functions of membrane progestin receptor alpha (mPRalpha) by progesterone receptor membrane component 1 (PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors. Endocrinology. 2014 Mar;155(3):1107-19.

Thunell S. Genetik och metabola fÃ¶rlopp bakom den akuta porfyriattacken - Mer Ã¤n hundra lÃ¤kemedel Ã¤r potentiellt livshotande vid akut porfyri. Lakartidningen. 2016 Sep 9;113.

Wei Y, Tang C, et al. A Molecular Aspect in the Regulation of Drug Metabolism: Does PXR-Induced Enzyme Expression Always Lead to Functional Changes in Drug Metabolism? Curr Pharmacol Rep. 2016 Aug;2(4):187-192.

Copyright 2007-2018 The Drug Database. All rights reserved.Page 5/6 Wu N, Yin L, et al. Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha. Genes Dev. 2009 Sep 15;23(18):2201-9